Bridging Biochemical and Clinical Disease Burden in Fabry Disease: A Comparative Analysis of Lyso-Gb3, MSSI, DS3, and...

Fabry disease is a rare X-linked lysosomal storage disorder characterized by progressive glycosphingolipid accumulation and multisystem organ involvement. Globotriaosylsphingosine (Lyso-Gb3) has emerged as a promising biomarker of disease burden; however, its relationship with validated clinical severity scoring systems remains incompletely understood. This study aimed to evaluate the associations between serum Lyso-Gb3 concentrations and the overall scores of three validated clinical severity assessment tools-the Mainz Severity Score Index (MSSI), Disease Severity Scoring System (DS3), and Fabry Stabilization Index (FASTEX)-in patients with Fabry disease. This retrospective observational study included 18 adult patients with genetically and/or enzymatically confirmed Fabry disease who were regularly followed at a tertiary referral center. Baseline and 12-month serum Lyso-Gb3 concentrations, MSSI scores, DS3 scores, and FASTEX values were evaluated. Correlations between Lyso-Gb3 concentrations and disease severity scores were assessed using Spearman correlation analysis. Exploratory sex-stratified analyses and univariable linear regression analyses were additionally performed to examine associations with disease severity; these analyses were considered hypothesis-generating because of the limited sample size. Median baseline Lyso-Gb3 concentration was 6.77 ng/mL (IQR: 3.94-50.10), median baseline MSSI score was 27.0 (IQR: 16.3-34.3), and median baseline DS3 score was 19.0 (IQR: 15.3-22.0). Significant reductions were observed in Lyso-Gb3 concentrations, MSSI scores, and DS3 scores after 12 months of follow-up (all p < 0.001). Baseline Lyso-Gb3 concentrations demonstrated strong positive correlations with baseline MSSI (ρ = 0.845, p < 0.001) and baseline DS3 scores (ρ = 0.854, p < 0.001), while no significant correlation was observed with FASTEX scores (ρ = -0.117, p = 0.644). Similar significant correlations were identified between 12-month Lyso-Gb3 concentrations and corresponding MSSI (ρ = 0.812, p < 0.001) and DS3 scores (ρ = 0.697, p = 0.001). In sex-stratified analyses, significant correlations between Lyso-Gb3 and disease severity scores were observed predominantly among male patients. In exploratory univariable linear regression analyses, baseline Lyso-Gb3 concentrations were strongly associated with baseline MSSI (R² = 0.758) and DS3 scores (R² = 0.579); however, these estimates should be interpreted cautiously because of the small sample size. Serum Lyso-Gb3 concentrations were strongly associated with MSSI and DS3 scores in this small retrospective cohort, whereas no statistically significant association was observed with FASTEX. The observed associations, particularly those derived from sex-stratified and regression analyses, should be considered exploratory and hypothesis-generating because of the limited sample size. Larger prospective multicenter studies are required to confirm the magnitude, independence, and clinical applicability of these relationships.